LEPR_HUMAN
ID LEPR_HUMAN Reviewed; 1165 AA.
AC P48357; Q13592; Q13593; Q13594; Q92919; Q92920; Q92921;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 222.
DE RecName: Full=Leptin receptor;
DE Short=LEP-R;
DE AltName: Full=HuB219;
DE AltName: Full=OB receptor;
DE Short=OB-R;
DE AltName: CD_antigen=CD295;
DE Flags: Precursor;
GN Name=LEPR; Synonyms=DB, OBR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS B AND E).
RC TISSUE=Brain;
RX PubMed=8548812; DOI=10.1016/0092-8674(95)90151-5;
RA Tartaglia L.A., Dembski M., Weng X., Deng N., Culpepper J., Devos R.,
RA Richards G.J., Campfield L.A., Clark F.T., Deeds J., Muir C., Sanker S.,
RA Moriarty A., Moore K.J., Smutko J.S., Mays G.G., Woolf E.A., Monroe C.A.,
RA Tepper R.I.;
RT "Identification and expression cloning of a leptin receptor, OB-R.";
RL Cell 83:1263-1271(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; B AND C), AND FUNCTION.
RC TISSUE=Fetal liver;
RX PubMed=8805376; DOI=10.1016/s0960-9822(02)70684-2;
RA Bennett B.D., Solar G.P., Yuan J.Q., Mathias J., Thomas G.R., Matthews W.;
RT "A role for leptin and its cognate receptor in hematopoiesis.";
RL Curr. Biol. 6:1170-1180(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; C AND D), AND VARIANTS ARG-109 AND
RP ARG-223.
RC TISSUE=Fetal liver;
RX PubMed=8616721; DOI=10.1038/nm0596-585;
RA Cioffi J.A., Shafer A.W., Zupancic T.J., Smith-Gbur J., Mikhail A.,
RA Platika D., Snodgrass H.R.;
RT "Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis
RT and reproduction.";
RL Nat. Med. 2:585-589(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM B), AND VARIANTS ARG-109 AND
RP ARG-223.
RX PubMed=9158141; DOI=10.1093/hmg/6.5.675;
RA Thompson D.B., Ravussin E., Bennett P.H., Bogardus C.;
RT "Structure and sequence variation at the human leptin receptor gene in lean
RT and obese Pima Indians.";
RL Hum. Mol. Genet. 6:675-679(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
RX PubMed=9061609; DOI=10.1677/jme.0.0180077;
RA Luoh S.-M., Di Marco F., Levin N., Armanini M., Xie M.H., Nelson C.,
RA Bennett G.L., Williams M., Spencer S.A., Gurney A., de Sauvage F.J.;
RT "Cloning and characterization of a human leptin receptor using a
RT biologically active leptin immunoadhesin.";
RL J. Mol. Endocrinol. 18:77-85(1997).
RN [6]
RP INVOLVEMENT IN LEPRD, AND FUNCTION.
RX PubMed=9537324; DOI=10.1038/32911;
RA Clement K., Vaisse C., Lahlou N., Cabrol S., Pelloux V., Cassuto D.,
RA Gourmelen M., Dina C., Chambaz J., Lacorte J.M., Basdevant A.,
RA Bougneres P., Lebouc Y., Froguel P., Guy-Grand B.;
RT "A mutation in the human leptin receptor gene causes obesity and pituitary
RT dysfunction.";
RL Nature 392:398-401(1998).
RN [7]
RP ALTERNATIVE SPLICING DUE TO AN ENDOGENOUS RETROVIRUS.
RX PubMed=9929394; DOI=10.1007/pl00013153;
RA Kapitonov V.V., Jurka J.;
RT "The long terminal repeat of an endogenous retrovirus induces alternative
RT splicing and encodes an additional carboxy-terminal sequence in the human
RT leptin receptor.";
RL J. Mol. Evol. 48:248-251(1999).
RN [8]
RP INTERACTION WITH PTPN11, AND MUTAGENESIS OF TYR-986; 1078-TYR-TYR-1079 AND
RP TYR-1141.
RX PubMed=9600917; DOI=10.1073/pnas.95.11.6061;
RA Carpenter L.R., Farruggella T.J., Symes A., Karow M.L., Yancopoulos G.D.,
RA Stahl N.;
RT "Enhancing leptin response by preventing SH2-containing phosphatase 2
RT interaction with Ob receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:6061-6066(1998).
RN [9]
RP GLYCOSYLATION AT ASN-23; ASN-41; ASN-56; ASN-73; ASN-81; ASN-98; ASN-187;
RP ASN-206; ASN-276; ASN-347; ASN-397; ASN-516; ASN-624; ASN-659; ASN-688;
RP ASN-697; ASN-728 AND ASN-750, DISULFIDE BONDS, AND PARTIAL PROTEIN
RP SEQUENCE.
RX PubMed=9786864; DOI=10.1074/jbc.273.44.28691;
RA Haniu M., Arakawa T., Bures E.J., Young Y., Hui J.O., Rohde M.F.,
RA Welcher A.A., Horan T.;
RT "Human leptin receptor. Determination of disulfide structure and N-
RT glycosylation sites of the extracellular domain.";
RL J. Biol. Chem. 273:28691-28699(1998).
RN [10]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=10896907; DOI=10.1136/gut.47.2.178;
RA Sobhani I., Bado A., Vissuzaine C., Buyse M., Kermorgant S., Laigneau J.P.,
RA Attoub S., Lehy T., Henin D., Mignon M., Lewin M.J.;
RT "Leptin secretion and leptin receptor in the human stomach.";
RL Gut 47:178-183(2000).
RN [11]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12504075; DOI=10.1016/s0006-291x(02)02838-3;
RA Zhao Y., Sun R., You L., Gao C., Tian Z.;
RT "Expression of leptin receptors and response to leptin stimulation of human
RT natural killer cell lines.";
RL Biochem. Biophys. Res. Commun. 300:247-252(2003).
RN [12]
RP TISSUE SPECIFICITY.
RX PubMed=16052473; DOI=10.1002/jcb.20521;
RA Solberg R., Aas V., Thoresen G.H., Kase E.T., Drevon C.A., Rustan A.C.,
RA Reseland J.E.;
RT "Leptin expression in human primary skeletal muscle cells is reduced during
RT differentiation.";
RL J. Cell. Biochem. 96:89-96(2005).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-276 AND ASN-516.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-276 AND ASN-397.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [15]
RP REVIEW ON FUNCTION, AND SUBUNIT.
RX PubMed=25232147; DOI=10.1530/joe-14-0404;
RA Allison M.B., Myers M.G. Jr.;
RT "20 years of leptin: connecting leptin signaling to biological function.";
RL J. Endocrinol. 223:T25-T35(2014).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-882, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
RP FUNCTION.
RX PubMed=25060689; DOI=10.1016/j.metabol.2014.06.010;
RA Cassano S., Pucino V., La Rocca C., Procaccini C., De Rosa V., Marone G.,
RA Matarese G.;
RT "Leptin modulates autophagy in human CD4+CD25- conventional T cells.";
RL Metabolism 63:1272-1279(2014).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 428-633 IN COMPLEX WITH ANTIBODY,
RP LEPTIN-BINDING REGION, DISULFIDE BONDS, AND FUNCTION.
RX PubMed=22405007; DOI=10.1016/j.str.2012.01.019;
RA Carpenter B., Hemsworth G.R., Wu Z., Maamra M., Strasburger C.J.,
RA Ross R.J., Artymiuk P.J.;
RT "Structure of the human obesity receptor leptin-binding domain reveals the
RT mechanism of leptin antagonism by a monoclonal antibody.";
RL Structure 20:487-497(2012).
RN [19]
RP VARIANT ARG-223.
RX PubMed=8666155; DOI=10.2337/diab.45.7.992;
RA Considine R.V., Considine E.L., Williams C.J., Hyde T.M., Caro J.F.;
RT "The hypothalamic leptin receptor in humans: identification of incidental
RT sequence polymorphisms and absence of the db/db mouse and fa/fa rat
RT mutations.";
RL Diabetes 45:992-994(1996).
RN [20]
RP VARIANTS ARG-109; ARG-204; ARG-223 AND ASN-656.
RX PubMed=9144432; DOI=10.1006/bbrc.1997.6430;
RA Echwald S.M., Soerensen T.D., Soerensen T.I., Tybjaerg-Hansen A.,
RA Andersen T., Chung W.K., Leibel R.L., Pedersen O.;
RT "Amino acid variants in the human leptin receptor: lack of association to
RT juvenile onset obesity.";
RL Biochem. Biophys. Res. Commun. 233:248-252(1997).
RN [21]
RP VARIANTS ARG-109; ARG-223 AND ASN-656.
RX PubMed=9287054; DOI=10.2337/diab.46.9.1509;
RA Chung W.K., Power-Kehoe L., Chua M., Chu F., Aronne L., Huma Z.,
RA Sothern M., Udall J.N., Kahle B., Leibel R.L.;
RT "Exonic and intronic sequence variation in the human leptin receptor gene
RT (LEPR).";
RL Diabetes 46:1509-1511(1997).
RN [22]
RP VARIANTS ARG-109; ARG-223 AND ASN-656.
RX PubMed=9175732; DOI=10.1093/hmg/6.6.869;
RA Gotoda T., Manning B.S., Goldstone A.P., Imrie H., Evans A.L.,
RA Strosberg A.D., McKeigue P.M., Scott J., Aitman T.J.;
RT "Leptin receptor gene variation and obesity: lack of association in a white
RT British male population.";
RL Hum. Mol. Genet. 6:869-876(1997).
RN [23]
RP VARIANTS ARG-109; ARG-223; ASN-656 AND THR-675.
RX PubMed=9860295; DOI=10.1007/s004390050867;
RA Roth H., Korn T., Rosenkranz K., Hinney A., Ziegler A., Kunz J.,
RA Siegfried W., Mayer H., Hebebrand J., Grzeschik K.-H.;
RT "Transmission disequilibrium and sequence variants at the leptin receptor
RT gene in extremely obese German children and adolescents.";
RL Hum. Genet. 103:540-546(1998).
RN [24]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-109 AND ARG-223.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S.,
RA Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A.,
RA DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
RN [25]
RP VARIANTS LEPRD HIS-422; GLY-604 AND PRO-786.
RX PubMed=25751111; DOI=10.1210/jc.2015-1036;
RA Huvenne H., Le Beyec J., Pepin D., Alili R., Kherchiche P.P., Jeannic E.,
RA Frelut M.L., Lacorte J.M., Nicolino M., Viard A., Laville M., Ledoux S.,
RA Tounian P., Poitou C., Dubern B., Clement K.;
RT "Seven novel deleterious LEPR mutations found in early-onset obesity: a
RT DeltaExon6-8 shared by subjects from Reunion Island, France, suggests a
RT founder effect.";
RL J. Clin. Endocrinol. Metab. 100:E757-E766(2015).
CC -!- FUNCTION: Receptor for hormone LEP/leptin (Probable) (PubMed:22405007).
CC On ligand binding, mediates LEP central and peripheral effects through
CC the activation of different signaling pathways such as JAK2/STAT3 and
CC MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-
CC regulating factor that induces a decrease in food intake and an
CC increase in energy consumption by inducing anorexinogenic factors and
CC suppressing orexigenic neuropeptides, also regulates bone mass and
CC secretion of hypothalamo-pituitary-adrenal hormones (By similarity)
CC (PubMed:9537324). In the periphery, increases basal metabolism,
CC influences reproductive function, regulates pancreatic beta-cell
CC function and insulin secretion, is pro-angiogenic and affects innate
CC and adaptive immunity (PubMed:25060689, PubMed:12504075,
CC PubMed:8805376). Control of energy homeostasis and melanocortin
CC production (stimulation of POMC and full repression of AgRP
CC transcription) is mediated by STAT3 signaling, whereas distinct signals
CC regulate NPY and the control of fertility, growth and glucose
CC homeostasis. Involved in the regulation of counter-regulatory response
CC to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has
CC a specific effect on T lymphocyte responses, differentially regulating
CC the proliferation of naive and memory T -ells. Leptin increases Th1 and
CC suppresses Th2 cytokine production (By similarity).
CC {ECO:0000250|UniProtKB:P48356, ECO:0000269|PubMed:12504075,
CC ECO:0000269|PubMed:22405007, ECO:0000269|PubMed:25060689,
CC ECO:0000269|PubMed:8805376, ECO:0000269|PubMed:9537324,
CC ECO:0000305|PubMed:25232147}.
CC -!- FUNCTION: [Isoform A]: May transport LEP across the blood-brain
CC barrier. Binds LEP and mediates LEP endocytosis. Does not induce
CC phosphorylation of and activate STAT3. {ECO:0000250|UniProtKB:P48356}.
CC -!- FUNCTION: [Isoform E]: Antagonizes Isoform A and isoform B-mediated LEP
CC binding and endocytosis. {ECO:0000250|UniProtKB:P48356}.
CC -!- SUBUNIT: Present as a mixture of monomers and dimers (Probable). The
CC phosphorylated receptor binds a number of SH2 domain-containing
CC proteins such as JAK2, STAT3, PTPN11, and SOCS3 (By similarity)
CC (PubMed:9600917). Interaction with SOCS3 inhibits JAK/STAT signaling
CC and MAPK cascade (By similarity). {ECO:0000250|UniProtKB:P48356,
CC ECO:0000269|PubMed:9600917, ECO:0000305|PubMed:25232147}.
CC -!- INTERACTION:
CC P48357; P62993: GRB2; NbExp=3; IntAct=EBI-518596, EBI-401755;
CC P48357; O15243: LEPROT; NbExp=2; IntAct=EBI-518596, EBI-15672507;
CC P48357-1; P48357-1: LEPR; NbExp=3; IntAct=EBI-7886250, EBI-7886250;
CC P48357-1; P48357-2: LEPR; NbExp=4; IntAct=EBI-7886250, EBI-7886387;
CC P48357-1; P48357-3: LEPR; NbExp=4; IntAct=EBI-7886250, EBI-7886448;
CC P48357-3; P48357-3: LEPR; NbExp=3; IntAct=EBI-7886448, EBI-7886448;
CC P48357-3; P0CG48: UBC; NbExp=2; IntAct=EBI-7886448, EBI-3390054;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19159218};
CC Single-pass type I membrane protein {ECO:0000305}. Basolateral cell
CC membrane {ECO:0000269|PubMed:19159218}.
CC -!- SUBCELLULAR LOCATION: [Isoform E]: Secreted
CC {ECO:0000250|UniProtKB:P48356}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=B; Synonyms=13.2, OBRb;
CC IsoId=P48357-1; Sequence=Displayed;
CC Name=A; Synonyms=6.4, HuB219.3;
CC IsoId=P48357-2; Sequence=VSP_001689, VSP_001690;
CC Name=C; Synonyms=12.1, OBRa;
CC IsoId=P48357-3; Sequence=VSP_001691, VSP_001692;
CC Name=D; Synonyms=HuB219.2;
CC IsoId=P48357-4; Sequence=VSP_001693, VSP_001694;
CC Name=E;
CC IsoId=P48357-5; Sequence=VSP_001688;
CC -!- TISSUE SPECIFICITY: Isoform A is expressed in fetal liver and in
CC hematopoietic tissues and choroid plexus. In adults highest expression
CC in heart, liver, small intestine, prostate and ovary. Low level in lung
CC and kidney. Isoform B is highly expressed in hypothalamus, but also in
CC skeletal muscle. Detected in fundic and antral epithelial cells of the
CC gastric mucosa (PubMed:19159218). Isoform B and isoform A are expressed
CC by NK cells (at protein level) (PubMed:12504075).
CC {ECO:0000269|PubMed:12504075, ECO:0000269|PubMed:16052473,
CC ECO:0000269|PubMed:19159218}.
CC -!- DOMAIN: The cytoplasmic domain may be essential for intracellular
CC signal transduction by activation of JAK tyrosine kinase and STATs.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-surface
CC receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- PTM: On ligand binding, phosphorylated on two conserved C-terminal
CC tyrosine residues (isoform B only) by JAK2. Tyr-986 is required for
CC complete binding and activation of PTPN11, ERK/FOS activation,for
CC interaction with SOCS3 and SOCS3 mediated inhibition of leptin
CC signaling. Phosphorylation on Tyr-1141 is required for STAT3
CC binding/activation. Phosphorylation of Tyr-1079 has a more accessory
CC role. {ECO:0000250|UniProtKB:P48356}.
CC -!- DISEASE: Leptin receptor deficiency (LEPRD) [MIM:614963]: A rare
CC disease characterized by normal levels of serum leptin, hyperphagia and
CC severe obesity from an early age. Additional features include
CC alterations in immune function, and delayed puberty due to
CC hypogonadotropic hypogonadism. {ECO:0000269|PubMed:25751111,
CC ECO:0000269|PubMed:9537324}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 2
CC subfamily. {ECO:0000305}.
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DR EMBL; U43168; AAA93015.1; -; mRNA.
DR EMBL; U66495; AAB07495.1; -; mRNA.
DR EMBL; U66496; AAB07496.1; -; mRNA.
DR EMBL; U66497; AAB07497.1; -; mRNA.
DR EMBL; U52912; AAC50509.1; -; mRNA.
DR EMBL; U52913; AAC50510.1; -; mRNA.
DR EMBL; U52914; AAC50511.1; -; mRNA.
DR EMBL; U59263; AAB09673.1; -; Genomic_DNA.
DR EMBL; U59248; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59249; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59250; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59252; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59253; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59254; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59255; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59256; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59257; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59258; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59259; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59260; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59261; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U59262; AAB09673.1; JOINED; Genomic_DNA.
DR EMBL; U50748; AAC23650.1; -; mRNA.
DR CCDS; CCDS30740.1; -. [P48357-2]
DR CCDS; CCDS30741.1; -. [P48357-3]
DR CCDS; CCDS55604.1; -. [P48357-4]
DR CCDS; CCDS631.1; -. [P48357-1]
DR RefSeq; NP_001003679.1; NM_001003679.3. [P48357-2]
DR RefSeq; NP_001003680.1; NM_001003680.3. [P48357-3]
DR RefSeq; NP_001185616.1; NM_001198687.1. [P48357-3]
DR RefSeq; NP_001185617.1; NM_001198688.1. [P48357-4]
DR RefSeq; NP_001185618.1; NM_001198689.1. [P48357-2]
DR RefSeq; NP_002294.2; NM_002303.5. [P48357-1]
DR PDB; 3V6O; X-ray; 1.95 A; A/B=428-633.
DR PDB; 6E2P; X-ray; 2.83 A; C/D=863-933.
DR PDBsum; 3V6O; -.
DR PDBsum; 6E2P; -.
DR AlphaFoldDB; P48357; -.
DR SMR; P48357; -.
DR BioGRID; 110144; 30.
DR CORUM; P48357; -.
DR DIP; DIP-6117N; -.
DR IntAct; P48357; 18.
DR MINT; P48357; -.
DR STRING; 9606.ENSP00000330393; -.
DR ChEMBL; CHEMBL5913; -.
DR DrugBank; DB05098; Leptin.
DR DrugBank; DB09046; Metreleptin.
DR DrugCentral; P48357; -.
DR GlyConnect; 1954; 17 N-Linked glycans (8 sites).
DR GlyGen; P48357; 19 sites, 17 N-linked glycans (8 sites).
DR iPTMnet; P48357; -.
DR PhosphoSitePlus; P48357; -.
DR BioMuta; LEPR; -.
DR DMDM; 116242617; -.
DR EPD; P48357; -.
DR jPOST; P48357; -.
DR MassIVE; P48357; -.
DR MaxQB; P48357; -.
DR PaxDb; P48357; -.
DR PeptideAtlas; P48357; -.
DR PRIDE; P48357; -.
DR ProteomicsDB; 55876; -. [P48357-1]
DR ProteomicsDB; 55877; -. [P48357-2]
DR ProteomicsDB; 55878; -. [P48357-3]
DR ProteomicsDB; 55879; -. [P48357-4]
DR ProteomicsDB; 55880; -. [P48357-5]
DR ABCD; P48357; 1 sequenced antibody.
DR Antibodypedia; 33374; 903 antibodies from 44 providers.
DR DNASU; 3953; -.
DR Ensembl; ENST00000344610.12; ENSP00000340884.8; ENSG00000116678.20. [P48357-4]
DR Ensembl; ENST00000349533.11; ENSP00000330393.7; ENSG00000116678.20. [P48357-1]
DR Ensembl; ENST00000371058.1; ENSP00000360097.1; ENSG00000116678.20. [P48357-4]
DR Ensembl; ENST00000371059.7; ENSP00000360098.3; ENSG00000116678.20. [P48357-3]
DR Ensembl; ENST00000371060.7; ENSP00000360099.3; ENSG00000116678.20. [P48357-2]
DR Ensembl; ENST00000616738.4; ENSP00000483390.1; ENSG00000116678.20. [P48357-2]
DR GeneID; 3953; -.
DR KEGG; hsa:3953; -.
DR MANE-Select; ENST00000349533.11; ENSP00000330393.7; NM_002303.6; NP_002294.2.
DR UCSC; uc001dcg.4; human. [P48357-1]
DR CTD; 3953; -.
DR DisGeNET; 3953; -.
DR GeneCards; LEPR; -.
DR HGNC; HGNC:6554; LEPR.
DR HPA; ENSG00000116678; Tissue enriched (liver).
DR MalaCards; LEPR; -.
DR MIM; 601007; gene.
DR MIM; 614963; phenotype.
DR neXtProt; NX_P48357; -.
DR OpenTargets; ENSG00000116678; -.
DR Orphanet; 179494; Obesity due to leptin receptor gene deficiency.
DR PharmGKB; PA229; -.
DR VEuPathDB; HostDB:ENSG00000116678; -.
DR eggNOG; ENOG502RK5B; Eukaryota.
DR GeneTree; ENSGT00730000111209; -.
DR HOGENOM; CLU_008491_0_0_1; -.
DR InParanoid; P48357; -.
DR OMA; FPPHCLF; -.
DR OrthoDB; 144839at2759; -.
DR PhylomeDB; P48357; -.
DR TreeFam; TF106501; -.
DR PathwayCommons; P48357; -.
DR Reactome; R-HSA-2586552; Signaling by Leptin. [P48357-1]
DR SignaLink; P48357; -.
DR SIGNOR; P48357; -.
DR BioGRID-ORCS; 3953; 11 hits in 1071 CRISPR screens.
DR ChiTaRS; LEPR; human.
DR GeneWiki; Leptin_receptor; -.
DR GenomeRNAi; 3953; -.
DR Pharos; P48357; Tclin.
DR PRO; PR:P48357; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P48357; protein.
DR Bgee; ENSG00000116678; Expressed in trabecular bone tissue and 196 other tissues.
DR Genevisible; P48357; HS.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0019955; F:cytokine binding; IBA:GO_Central.
DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0038021; F:leptin receptor activity; IDA:ARUK-UCL.
DR GO; GO:0017046; F:peptide hormone binding; IBA:GO_Central.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; TAS:ProtInc.
DR GO; GO:0001525; P:angiogenesis; IMP:UniProtKB.
DR GO; GO:0098868; P:bone growth; ISS:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:ProtInc.
DR GO; GO:0014009; P:glial cell proliferation; IEA:Ensembl.
DR GO; GO:0006094; P:gluconeogenesis; IEA:Ensembl.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0005977; P:glycogen metabolic process; IEA:Ensembl.
DR GO; GO:0033210; P:leptin-mediated signaling pathway; IDA:ARUK-UCL.
DR GO; GO:0007275; P:multicellular organism development; TAS:ProtInc.
DR GO; GO:0010507; P:negative regulation of autophagy; IDA:UniProtKB.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IEA:Ensembl.
DR GO; GO:0051346; P:negative regulation of hydrolase activity; IEA:Ensembl.
DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:ARUK-UCL.
DR GO; GO:0046850; P:regulation of bone remodeling; ISS:UniProtKB.
DR GO; GO:0060259; P:regulation of feeding behavior; ISS:UniProtKB.
DR GO; GO:0051049; P:regulation of transport; IDA:ARUK-UCL.
DR GO; GO:0044321; P:response to leptin; ISS:UniProtKB.
DR GO; GO:0019953; P:sexual reproduction; ISS:UniProtKB.
DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB.
DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL.
DR CDD; cd00063; FN3; 3.
DR Gene3D; 2.60.40.10; -; 7.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR003529; Hematopoietin_rcpt_Gp130_CS.
DR InterPro; IPR003531; Hempt_rcpt_S_F1_CS.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR010457; IgC2-like_lig-bd.
DR InterPro; IPR041182; LEP-R_IGD.
DR InterPro; IPR015752; Lep_receptor.
DR PANTHER; PTHR23036:SF109; PTHR23036:SF109; 1.
DR Pfam; PF06328; Lep_receptor_Ig; 1.
DR Pfam; PF18589; ObR_Ig; 2.
DR SMART; SM00060; FN3; 4.
DR SUPFAM; SSF49265; SSF49265; 4.
DR PROSITE; PS50853; FN3; 3.
DR PROSITE; PS01353; HEMATOPO_REC_L_F2; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin domain; Membrane; Obesity; Phosphoprotein; Receptor;
KW Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..21
FT CHAIN 22..1165
FT /note="Leptin receptor"
FT /id="PRO_0000010904"
FT TOPO_DOM 22..839
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 840..862
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 863..1165
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 239..333
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 331..429
FT /note="Ig-like"
FT DOMAIN 539..634
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 639..732
FT /note="Fibronectin type-III 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 740..833
FT /note="Fibronectin type-III 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 467..484
FT /note="Leptin-binding"
FT /evidence="ECO:0000305|PubMed:22405007"
FT REGION 893..898
FT /note="Required for JAK2 activation"
FT /evidence="ECO:0000250|UniProtKB:P48356"
FT REGION 898..906
FT /note="Required for STAT3 phosphorylation"
FT /evidence="ECO:0000250|UniProtKB:P48356"
FT MOTIF 622..626
FT /note="WSXWS motif"
FT MOTIF 871..879
FT /note="Box 1 motif"
FT MOD_RES 882
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 986
FT /note="Phosphotyrosine; by JAK2"
FT /evidence="ECO:0000250|UniProtKB:P48356"
FT MOD_RES 1079
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P48356"
FT MOD_RES 1141
FT /note="Phosphotyrosine; by JAK2"
FT /evidence="ECO:0000250|UniProtKB:P48356"
FT CARBOHYD 23
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 41
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 56
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 73
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 81
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 98
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 187
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 206
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 276
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:9786864"
FT CARBOHYD 347
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 397
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218,
FT ECO:0000269|PubMed:9786864"
FT CARBOHYD 516
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:9786864"
FT CARBOHYD 624
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 659
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 688
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 697
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 728
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT CARBOHYD 750
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:9786864"
FT DISULFID 37..90
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 89..99
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 131..142
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 186..196
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 188..193
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 352..412
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 413..418
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 436..447
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 473..528
FT /evidence="ECO:0000269|PubMed:22405007"
FT DISULFID 488..498
FT /evidence="ECO:0000269|PubMed:22405007"
FT VAR_SEQ 840..1165
FT /note="Missing (in isoform E)"
FT /evidence="ECO:0000303|PubMed:8548812"
FT /id="VSP_001688"
FT VAR_SEQ 892..958
FT /note="PETFEHLFIKHTASVTCGPLLLEPETISEDISVDTSWKNKDEMMPTTVVSLL
FT STTDLEKGSVCISDQ -> MLEGSMFVKSHHHSLISSTQGHKHCGRPQGPLHRKTRDLC
FT SLVYLLTLPPLLSYDPAKSPSVRNTQE (in isoform C)"
FT /evidence="ECO:0000303|PubMed:8616721,
FT ECO:0000303|PubMed:8805376"
FT /id="VSP_001691"
FT VAR_SEQ 892..906
FT /note="PETFEHLFIKHTASV -> KMPGTKELLGGGWLT (in isoform D)"
FT /evidence="ECO:0000303|PubMed:8616721"
FT /id="VSP_001693"
FT VAR_SEQ 892..896
FT /note="PETFE -> RTDIL (in isoform A)"
FT /evidence="ECO:0000303|PubMed:8616721,
FT ECO:0000303|PubMed:8805376, ECO:0000303|PubMed:9061609"
FT /id="VSP_001689"
FT VAR_SEQ 897..1165
FT /note="Missing (in isoform A)"
FT /evidence="ECO:0000303|PubMed:8616721,
FT ECO:0000303|PubMed:8805376, ECO:0000303|PubMed:9061609"
FT /id="VSP_001690"
FT VAR_SEQ 907..1165
FT /note="Missing (in isoform D)"
FT /evidence="ECO:0000303|PubMed:8616721"
FT /id="VSP_001694"
FT VAR_SEQ 959..1165
FT /note="Missing (in isoform C)"
FT /evidence="ECO:0000303|PubMed:8616721,
FT ECO:0000303|PubMed:8805376"
FT /id="VSP_001692"
FT VARIANT 109
FT /note="K -> R (in dbSNP:rs1137100)"
FT /evidence="ECO:0000269|PubMed:18987736,
FT ECO:0000269|PubMed:8616721, ECO:0000269|PubMed:9144432,
FT ECO:0000269|PubMed:9158141, ECO:0000269|PubMed:9175732,
FT ECO:0000269|PubMed:9287054, ECO:0000269|PubMed:9860295"
FT /id="VAR_002703"
FT VARIANT 124
FT /note="D -> G (in dbSNP:rs35573508)"
FT /id="VAR_049167"
FT VARIANT 204
FT /note="K -> R (in dbSNP:rs146442768)"
FT /evidence="ECO:0000269|PubMed:9144432"
FT /id="VAR_002704"
FT VARIANT 223
FT /note="Q -> R (in dbSNP:rs1137101)"
FT /evidence="ECO:0000269|PubMed:18987736,
FT ECO:0000269|PubMed:8616721, ECO:0000269|PubMed:8666155,
FT ECO:0000269|PubMed:9144432, ECO:0000269|PubMed:9158141,
FT ECO:0000269|PubMed:9175732, ECO:0000269|PubMed:9287054,
FT ECO:0000269|PubMed:9860295"
FT /id="VAR_002705"
FT VARIANT 422
FT /note="Y -> H (in LEPRD; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25751111"
FT /id="VAR_075723"
FT VARIANT 503
FT /note="I -> V (in dbSNP:rs13306526)"
FT /id="VAR_028201"
FT VARIANT 604
FT /note="C -> G (in LEPRD; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25751111"
FT /id="VAR_075724"
FT VARIANT 656
FT /note="K -> N (in dbSNP:rs1805094)"
FT /evidence="ECO:0000269|PubMed:9144432,
FT ECO:0000269|PubMed:9175732, ECO:0000269|PubMed:9287054,
FT ECO:0000269|PubMed:9860295"
FT /id="VAR_002706"
FT VARIANT 675
FT /note="S -> T (in dbSNP:rs373154589)"
FT /evidence="ECO:0000269|PubMed:9860295"
FT /id="VAR_002707"
FT VARIANT 699
FT /note="T -> M (in dbSNP:rs34499590)"
FT /id="VAR_049168"
FT VARIANT 786
FT /note="L -> P (in LEPRD; unknown pathological significance;
FT dbSNP:rs1303050393)"
FT /evidence="ECO:0000269|PubMed:25751111"
FT /id="VAR_075725"
FT MUTAGEN 986
FT /note="Y->F: Greatly reduced PTPN11 binding; no PTPN11
FT phosphorylation; no effect on STAT3 phosphorylation."
FT /evidence="ECO:0000269|PubMed:9600917"
FT MUTAGEN 1078..1079
FT /note="YY->FF: No effect on PTPN11 nor STAT3
FT phosphorylation."
FT /evidence="ECO:0000269|PubMed:9600917"
FT MUTAGEN 1141
FT /note="Y->F: No effect on PTPN11 phosphorylation; no STAT3
FT phosphorylation."
FT /evidence="ECO:0000269|PubMed:9600917"
FT CONFLICT 85
FT /note="T -> A (in Ref. 3; AAC50509/AAC50510/AAC50511)"
FT /evidence="ECO:0000305"
FT CONFLICT 976
FT /note="D -> A (in Ref. 1; AAA93015 and 4; AAB09673)"
FT /evidence="ECO:0000305"
FT STRAND 435..438
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 445..449
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 461..468
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 484..486
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 488..490
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 496..500
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 509..517
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 527..529
FT /evidence="ECO:0007829|PDB:3V6O"
FT HELIX 531..534
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 544..548
FT /evidence="ECO:0007829|PDB:3V6O"
FT TURN 549..552
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 553..557
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 568..580
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 584..588
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 595..598
FT /evidence="ECO:0007829|PDB:3V6O"
FT STRAND 607..615
FT /evidence="ECO:0007829|PDB:3V6O"
FT HELIX 878..880
FT /evidence="ECO:0007829|PDB:6E2P"
FT STRAND 881..883
FT /evidence="ECO:0007829|PDB:6E2P"
SQ SEQUENCE 1165 AA; 132494 MW; CAA03BEAF2602D0A CRC64;
MICQKFCVVL LHWEFIYVIT AFNLSYPITP WRFKLSCMPP NSTYDYFLLP AGLSKNTSNS
NGHYETAVEP KFNSSGTHFS NLSKTTFHCC FRSEQDRNCS LCADNIEGKT FVSTVNSLVF
QQIDANWNIQ CWLKGDLKLF ICYVESLFKN LFRNYNYKVH LLYVLPEVLE DSPLVPQKGS
FQMVHCNCSV HECCECLVPV PTAKLNDTLL MCLKITSGGV IFQSPLMSVQ PINMVKPDPP
LGLHMEITDD GNLKISWSSP PLVPFPLQYQ VKYSENSTTV IREADKIVSA TSLLVDSILP
GSSYEVQVRG KRLDGPGIWS DWSTPRVFTT QDVIYFPPKI LTSVGSNVSF HCIYKKENKI
VPSKEIVWWM NLAEKIPQSQ YDVVSDHVSK VTFFNLNETK PRGKFTYDAV YCCNEHECHH
RYAELYVIDV NINISCETDG YLTKMTCRWS TSTIQSLAES TLQLRYHRSS LYCSDIPSIH
PISEPKDCYL QSDGFYECIF QPIFLLSGYT MWIRINHSLG SLDSPPTCVL PDSVVKPLPP
SSVKAEITIN IGLLKISWEK PVFPENNLQF QIRYGLSGKE VQWKMYEVYD AKSKSVSLPV
PDLCAVYAVQ VRCKRLDGLG YWSNWSNPAY TVVMDIKVPM RGPEFWRIIN GDTMKKEKNV
TLLWKPLMKN DSLCSVQRYV INHHTSCNGT WSEDVGNHTK FTFLWTEQAH TVTVLAINSI
GASVANFNLT FSWPMSKVNI VQSLSAYPLN SSCVIVSWIL SPSDYKLMYF IIEWKNLNED
GEIKWLRISS SVKKYYIHDH FIPIEKYQFS LYPIFMEGVG KPKIINSFTQ DDIEKHQSDA
GLYVIVPVII SSSILLLGTL LISHQRMKKL FWEDVPNPKN CSWAQGLNFQ KPETFEHLFI
KHTASVTCGP LLLEPETISE DISVDTSWKN KDEMMPTTVV SLLSTTDLEK GSVCISDQFN
SVNFSEAEGT EVTYEDESQR QPFVKYATLI SNSKPSETGE EQGLINSSVT KCFSSKNSPL
KDSFSNSSWE IEAQAFFILS DQHPNIISPH LTFSEGLDEL LKLEGNFPEE NNDKKSIYYL
GVTSIKKRES GVLLTDKSRV SCPFPAPCLF TDIRVLQDSC SHFVENNINL GTSSKKTFAS
YMPQFQTCST QTHKIMENKM CDLTV
